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Acute Lymphoblastic Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Several genetic BCP-ALL subtypes with no single defining chromosomal alteration have been recognized in about 25% childhood and a higher proportion of adults. These include the Ph-like (BCR-ABL1-like), which has a similar gene expression profile as BCR-ABL1-positive ALL, but do not have BCR-ABL1 and are recognized in the 2016 WHO classification. Genome-wide approaches have also demonstrated a high frequency of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS, and PAX5 deletions. Multivariate analysis confirms the very poor prognosis conferred by any genetic alteration of IKZF1 and the unfavourable response to current standard therapy.
B-Lymphoblastic Leukemia/Lymphoma
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
IKZF1 deletions (and sequence mutations) occur in ~15% of childhood ALLs and are associated with high-risk disease and treatment resistance. IKZF1 encodes IKAROS, the member of a family of zinc finger transcription factors that are required for the development of all lymphoid lineages. The IKZF1 alterations observed in ALL include focal or broad deletions that result in loss of function and internal deletions of coding exons 4–7. IKZF1 alterations are present in >70% of BCR–ABL1+ ALLs, including de novo ALL and chronic myeloid leukemia at progression to lymphoid blast crisis [59]. IKZF1-mutated cases exhibit a gene expression profile similar to BCR–ABL1+ ALL and harbor novel kinase-activating mutations and rearrangements.
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
In B-ALL/B-LBL, the various cytogenetic abnormalities can conveniently be divided into two groups: those with numerical chromosomal abnormnalities; hypodiploidy, high hyperdiploidy with either less than 40 chromoosmes or more than 50 chromosomes, respectively, and those with structural chromosomal abnormalities including translocations. High hyperdiploidy (51–65 chromosomes) is found in up to 30% of children and 10% of adults with ALL and is associated with an excellent prognosis because the lymphoblasts demonstrate unique susceptibility to anti-metabolites.61 The observation that about half of these patients develop additional cytogenetic abnormalities, in particular duplications of chromosome 1q and isochromosome of 17q, has led to the hypothesis of a probable ‘two-hit’ genetic event resulting in a transformed phenotype that may not respond to therapy as well. Approximately 25%–30% of adults and 3% of children have a Philadelphia (Ph) chromosome [t(9;22)(q34;q11)]. One-third of Ph-positive ALL patients have BCR-ABL1 transcripts indistinguishable from those found in CML. The remaining two-thirds have a breakpoint in the first intron of the BCR1 gene (between e1 and e2) in an area designated the minor breakpoint cluster region (m-bcr); this is transcribed as an e1a2 mRNA, which encodes a 190 kD protein (p190BCR-ABL1), in contrast to the p210BCR-ABL1 typical of CML.62 Genomewide approaches have demonstrated a high frequency of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS, and PAX5 deletions, of which IKZF1 deletions portend a poor prognosis.63 Multivariate analysis confirms the very poor prognosis conferred by any genetic alteration of IKZF1 and the unfavourable response to current standard therapy.64 A recently recognized genetic subtype, known as ‘BCR-ABL1-like’, shows a similar gene expression signature to BCR-ABL1-positive ALL and shares the same poor-risk features. Uniquely, this is associated with a high incidence of IKZF1 deletions, deregulated CRLF2 and JAK mutations.
Primary Immunodeficiency and Thrombocytopenia
Published in International Reviews of Immunology, 2022
Maryam Mohtashami, Azadehsadat Razavi, Hassan Abolhassani, Asghar Aghamohammadi, Reza Yazdani
IKAROS is a zinc-finger transcription factor that is not only expressed in all HSCs, but also acts as a key component in the early stages of B- cell development, specification and its commitment. IKAROS structure contains two parts. The first part is characterized by the N-terminal DNA-binding motif and C2H2 zinc-finger domain locating in this area. The latter part is C-terminal, which is responsible for Ikaros family members and connecting via two zinc-finger domains. Two C-terminal zinc-finger domains are recruited for homologous or heterogeneous dimers formation and four germlines heterozygous IKAROS variants affect this region via haploinsuffiency [118, 119]. IKZF1 gene encodes the transcription factor IKAROS. This molecule acts as a regulator of B- cell differentiation [120]. Mutation in the IKZF1 gene leads to B- cell deficiency. In addition to B-cell deficiency, malignancy progressions such as hematological malignancies (leukemia) and solid tumors are accompanied by IKAROS mutation. The lack of IKAROS, for instance, is associated with downregulation of IL-7 receptor on naïve T cell surface or reduction of B cell progenitors in the bone marrow [118, 119]. Studies have highlighted the importance of IKAROS deficiency in boosting megakaryocyte production. However, S. Malinge supposed that IKZF5 is associated with mild thrombocytopenia and there is still no evidence to establish whether IKZF1 involve in platelet development [64, 120–122].
Clinical value of RAG1 expression and IKZF1 deletions in Philadelphia negative pediatric B cell precursor acute lymphoblastic leukemia
Published in Pediatric Hematology and Oncology, 2020
Salah Aref, Nada Khaled, Nadia El Menshawy, Mohamed Sabry, Mohamed Al Agder
IKZF1 (IKAROS) acts as transcription factor which has an important role in the regulation of lymphoid differentiation. The IKZF1 gene at 7p12.2 that codes for IKAROS acts as a transcription factor in hematopoiesis and involved primarily in lymphoid differentiation. Its importance is underlined by the fact that deregulation of IKAROS results in leukemia in both mice and men3 and was reported to be frequently deleted or mutated in BCP–ALL.4 The gene for IKZF1 consists of eight exons, spanning of 62 kilobase, and coding for a 519‐amino acid protein. Exon 1 together with promotor region are not translated but the transcription of the gene; the function of exons 2, 3, and 7 are not known. The remaining exons are crucial for proper function of IKAROS: exons 4–6 encode the four N‐terminal zinc fingers that are required for DNA binding and exon 8 codes for the two C‐terminal zinc fingers that are used by IKAROS to dimerize either with itself or with other members of its family.5,6 Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR–ABL1+ (Ph+) and Ph-like disease subtypes.7–9IKZF1 alterations in B-ALL lead to the induction of multiple genes associated with the proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.9 IKZF1 mutations are common in adults with B-cell ALL and are also associated with poor prognosis in persons with concurrent BCRABL1.10–12
The prognostic and predictive value of IKZF1 and IKZF3 expression in T-cells in patients with multiple myeloma
Published in OncoImmunology, 2018
Mohamed H. S. Awwad, Katharina Kriegsmann, Julian Plaumann, Michael Benn, Jens Hillengass, Marc S. Raab, Uta Bertsch, Markus Munder, Katja Weisel, Hans Jürgen Salwender, Mathias Hänel, Roland Fenk, Jan Dürig, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Hundemer
The post-transcriptional regulation of IKZF1/3 is poorly understood, heterodimerization with other proteins is thought to be one of the mechanisms by which IKZF1/3 functions are regulated.7-9 Spleen tyrosine kinase (SYK) and Bruton’s Tyrosine Kinase (BTK) are found to phosphorylate unique sites in the zinc finger domain of IKZF1 and therefore increase its nuclear localization and DNA binding activity.7,10 Moreover, the phosphorylation of IKZF1 by Casein Kinase II (CK2) at its C-terminal region regulates its ability to control G1/S cell cycle progression.11